Method for treating Meniere&#39;s disease

ABSTRACT

A medicine for the treatment of Meniere&#39;s disease containing, as an active ingredient, erythritol which is capable of significantly reducing the endolymphatic pressure by oral administration of a therapeutically effective amount of erythritol as an active substance.

DESCRIPTION

1. Technical Field

The present invention relates to a medicine for the treatment ofMeniere's disease containing erythritol as an active ingredient.

2. Background Art

Meniere's disease is a disease of unknown cause, but it has beenreported to be an endolymphatic hydrops by nature. It is believed thatendolymphatic fluid accumulates due to excess production ofendolymphatic fluid or due to disorders in absorption, whereby theendolymphatic hydrops is formed and the Reissner's membranes of thecochlear duct is risen and, as a result, symptoms such as ringing of theears, hearing difficulties, dizziness, and a feeling of blocked ears aregenerated.

In the past, as a medicine for the treatment of Meniere's disease, theosmotic pressure diuretic medicine, Isosorbide (i.e.,1,4:3,6-dianhydro-D-sorbitol) has been used as an oral administrationagent for the purpose of alleviating the endolymphatic hydrops. However,the osmotic pressure diuretic medicine, Isosorbide currently, which isclinically applied as a medicine for the treatment of Meniere's diseasehas difficulties in the viewpoint of taste. Further, it is a liquid, andtherefore, there is the problem of inconvenience in the transportation.

DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to provide a medicinefor the treatment of Meniere's disease which is superior in theviewpoint of taste, is capable of reducing the amount of the medicine tobe administered by improving the type of formulation, and is easy totake by patients.

In accordance with the present invention, there is provided a medicinefor the treatment of Meniere's disease comprising erythritol as anactive ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be explained in further detail withreference to the drawings.

FIG. 1 is a view of the effect of alleviation of a hydrops witherythritol and Isosorbide in an endolymphatic hydrops model (an averagevalue±standard error). In FIG. 1, D.W. is a symbol showing the distilledwater administration group, * is a symbol showing the presence of asignificant difference at the significant test of p<0.05, and ** shows asignificant difference at the significant test of p<0.01.

FIG. 2 is a view of the action of erythritol in decreasing theendolymphatic pressure (endolymphatic differential pressure) for anendolymphatic hydrops model (an average value±standard error). In theFigure, D.W. is a symbol showing the distilled water administrationgroup, * is a symbol showing the presence of a significant differencetest at p<0.05, and ** shows a significant difference at p<0.01.

FIG. 3 is a view of the action of erythritol in increasing the plasmaosmotic pressure in anesthetized guinea pigs (an average value±standarderror). In the Figure, D.W. is a symbol showing the distilled waterintraduodenum administration group, and ** is a symbol showing thepresence of a significant difference at the signification test ofp<0.01.

BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors engaged in various studies to find a medicine forthe treatment of Meniere's disease superior to Isosorbide in viewpointof taste and, as a result found that by intraduodenum administration ofan erythritol aqueous solution, the endolymphatic pressure could bedecreased quickly and found that, when using an aqueous erythritolsolution as an oral agent, there is an equivalent effect as withisosorbide in viewpoint of dosage, whereby the present invention wascompleted.

According to the present invention, there is provided a medicine for thetreatment of Meniere's disease having erythritol as an activeingredient. By orally ingesting a therapeutically effective amount oferythritol as an active ingredient, it is possible to significantlydecrease the endolymphatic pressure.

The medicine for treatment of Meniere's disease according to the presentinvention is used in an amount, converted to erythritol, of normally 0.5to 3 g/kg, preferably 0.8 to 1.5 g/kg, per kg body weight, and is takenone to three times a day depending on the symptoms.

Erythritol has the characteristics of having a refreshing sweet taste,being noncarious, and having zero calories, and therefore, is used invarious confectioneries and beverages as a sweetener (or foodingredient). The toxicity thereof is extremely low. This is clear fromthe results of pilot acute toxicity tests using rats (LD₅₀ value (g/kg),oral administration: males 11.8, females 9.5, intravenousadministration: males 6.1, females 5.4) (see Japanese Examined PatentPublication (Kokoku) No. 7-103017).

The medicine for treatment of Meniere's disease according to the presentinvention may be administered by all types of preparations as oralagents such as, for example, liquids, powders, granules, suspensions,tablets, capsules, dry syrups, etc. However, since the amount to beadministered becomes large, powders, granules, and suspensions arepreferable. In this way, in a preferable aspect of the presentinvention, the medicine for treatment of Meniere's disease according tothe present invention is composed of erythritol as an active ingredientand, if desired, a base material. The concentration of the erythritol inthe medicine composition is not particularly limited, but preferably is90 to 100% by weight of the composition.

A suspension may be produced by adding and mixing to the erythritol,normally 0.1 to 10% by weight, preferably 0.2 to 1% by weight, pererythritol, of a suspension of one or more types of a suspending agent(or base material) selected from the group consisting of polyvinylpyrrolidone, sodium carboxymethyl cellulose, carboxyvinyl polymer,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, xanthane gum,gelatin, tragacanth gum, crystalline cellulose, alginate, agar, etc.Further, it is possible to add a flavor (e.g., 0.001 to 0.1% by weight)or a sweetener (e.g., 0.1 to 1% by weight) to the suspension to improvethe ease of the administration.

A granular preparation may be produced by, for example, adding water,ethanol, or a mixed solution thereof etc. to erythritol, mixing them ina kneader, extruding the resultant mixture by the means of an extrusiongranulator etc., drying the extrudate and sieving it after drying toobtain granules, then adding a small amount of Carbopol 971P(“trademark” for carboxyvinyl polymer made by B.F. Goodrich) andmagnesium stearate etc. followed by mixing to obtain the granules. Thegranular preparation thus obtained can be ingested as it is or bysuspension in a suitable amount of water.

A high density granular preparation can be produced, without usingwater, by mixing erythritol, a gum such as xanthane gum and tragacanthgum, and a lubricant such as calcium stearate and extruding the mixtureunder a high pressure, etc. The obtained high density granularpreparation thus obtained may be administered as it is or aftersuspended in water.

The medicine for treatment of Meniere's disease according to the presentinvention may have suitably compounded thereinto, to an extent as longas the object of the present invention is not impaired, other medicinalingredients, for example, a sympathetic nerve β-agonist, a vasodilative,or a cerebral circulation improving drug as a medicine having an actionimproving the circulation in the inner ear, a diuretic or adrenacorticalsteroid as a medicine for alleviating hydrolabyrinth, and a sedative,tranquilizer, antiemetic, anti-dizziness agent, or autonomic regulatoras a medicine for sedation or control of nausea.

EXAMPLES

The present invention will now be explained in further detail to clarifythe effects of the present invention with reference to pharmacologicaltests of the preparations and the Preparations Examples, but these aremerely illustrations. The present invention is by no means limitedthereto.

Test Example 1 (Endolymphatic Pressure Reducing Action)

Test Method

(Animals)

Guinea pigs (Hartley strain, body weights of 300 to 500 g) were used asgroups each having 13 to 14 pigs.

(Test Medicines)

(1) Erythritol: The amounts of erythritol administered were threedosages of 0.7, 1.4, and 2.8 g/kg. These were dissolved in, and dilutedwith, distilled water to the administration volumes of 8 ml/kg.

(2) Isosorbide: The amounts of isosorbide administered as well werethree dosages of 0.7, 1.4, and 2.8 g/kg. These were dissolved in, anddiluted with, distilled water to the administration volumes of 8 ml/kg.

(Endolymphatic Sac Silver Nitrate Corrosion Method)

According to the method of Yazawa (Daishiro Yazawa, Jibi Rinsho, 74:2450 to 2506 (1981)), a small amount (30 to 50 μl) of a 10% aqueoussilver nitrate solution was surgically injected into the endolymphaticsac and, then, the incision sewn closed. Individuals after more than 21days from the surgery were made to fast for at least 18 hours and, then,orally given the test medicine. One hour after the administration, theexistence of urination was confirmed, then the animal was fixed underperfusion under anesthesia and the degree of hydrops in the cochlearduct was judged according to the criteria of Paparella (Paparella, M. M.et al.: Laryngoscope, 89:43-54 (1979) as:

None: 0, Slight: 1, Medium: 2, Severe: 3 The degree of advance of theeight Reissner's membranes in the cochlear duct which could berecognized as tissue sections was scored. The average was used as theresult of the test of the individual.

Results

As a result of the test, the hydrops score of the distilled wateradministration group in the endolymphatic hydrops model was 1.66±0.27.For erythritol, a dosage-dependent reduction in the hydrops score due tooral administration of 0.7 g/kg, 1.4 g/kg, and 2.8 g/kg to 1.45±0.49,1.21±0.31, 0.70±0.25 was recognized. In the 2.8 g/kg administrationgroup, the hydrops score was significantly decreased compared with thedistilled water administration group. For Isosorbide, a dosage-dependentdecrease in the hydrops score due to oral administration of 0.7 g/kg,1.4 g/kg, and 2.8 g/kg to 1.33±0.32, 1.01±0.38, and 0.72±0.30 wasrecognized. In the 2.8 g/kg group, the edema score was significantlydecreased compared with the distilled water group.

FIG. 1 shows the results of the test for 0.7 g/kg, 1.4 g/kg, and 2.8g/kg of erythritol and for 0.7 g/kg, 1.4 g/kg, and 2.8 g/kg ofIsosorbide.

Test Example 2 (Endolymphatic Pressure Reducing Action)

Test Method

(Animals)

Guinea pigs (Hartley strain, body weights of 300 to 500 g) were used asgroups each having three to five pigs.

(Test Medicines)

Erythritol: The amounts of erythritol administered were two dosages of1.4 and 2.8 g/kg. These were dissolved in, and diluted with, distilledwater to the administration volumes of 8 ml/kg.

(Endolymphatic Sac Silver Nitrate Corrosion Method and EndolymphaticPressure Measurement Method)

According to the method of Yazawa (Daishiro Yazawa, Jibi Rinsho, 74:2450 to 2506 (1981)), a small amount (30 to 50 μl) of a 10% aqueoussilver nitrate solution was surgically injected into the endolymphaticsac and then the incision sewn closed. Individuals after more than 21days from surgery were anesthetized and the respiratory tract secured,then a cannula was inserted into the duodenum and the test medicineinjected.

The trunk was held in the prone position, the rear of the middle-earcavity was cut open, and the cochlear duct was exposed. The cochlearbasal rotatory tympanic wall or stria vascularis confirmed from theround window was cut open by a microdrill, then a glass capillaryconnected to a polyethylene tube was inserted into the basal rotatorycochlear duct using a micromanipulator and affixed air-tightly.

The inside of the closed circuit was filled, in advance, withendolymphatic equivalent solution, the polyethylene tube was connectedto a pressure transducer, and the results recorded in a recticorderthrough an amplifier.

The test substance started to be administered after confirmation of thestability of the endolymphatic pressure.

Results

As a result of the above test, no change could be recognized in theendolymphatic pressure of the distilled water group. A dosage-dependentfall in the endolymphatic pressure due to the administration of 1.4 g/kgand 2.8 g/kg of erythritol into the duodenum was observed. In both the1.4 g/kg group and the 2.8 g/kg group, the endolymphatic pressure wassignificantly decreased, compared with the distilled water group.

FIG. 2 shows the results of tests using distilled water and 1.4 g/kg and2.8 g/kg of erythritol.

Test Example 3 (Action Raising Plasma Osmotic Pressure)

Test Method

(Animals)

Guinea pigs (Hartley strain, body weights of 300 to 500 g) were used asgroups each having five pigs.

(Test Medicine)

Erythritol: The amounts of erythritol administered were two dosages of1.4 g/kg and 2.8 g/kg. These were dissolved in, and diluted with,distilled water to the administration volumes of 8 ml/kg.

(Method)

Normal guinea pigs were each anesthetized and their respiratory tractssecured, then a canular was inserted in the left carotid artery and usedto sample blood. Further, a cannula was inserted into the duodenum andused to inject the test medicine. The trunk was held in the supineposition and the blood was sampled before administration (pre). Theblood was then sampled 15 minutes, 30 minutes, 60 minutes, 120 minutes,and 180 minutes after administration of the test substance. Aftersampling, to secure the amount of body fluid, physiological saline ofthe same amount as the blood sampled was injected from the bloodsampling cannula. The sampled blood was separated by centrifugation,then the plasma was taken and the plasma osmotic pressure was measuredusing an osmotic pressure meter.

Results

As a result of the above test, no change could be recognized in theplasma osmotic pressure of the distilled water group. It was recognizedby the administrations of 1.4 g/kg and 2.8 g/kg of erythritol that adosage-dependent rise in the plasma osmotic pressure after 15 minutesfrom administration of the medicine into the duodenum peaked at 30minutes and 60 minutes after administration. In particular, in the 2.8g/kg erythritol group, a significant increase in the plasma osmoticpressure continued until 180 minutes after administration.

FIG. 3 shows the results of tests using distilled water and 1.4 g/kg and2.8 g/kg of erythritol.

Example 1 (Suspension)

2 g of Carbopol 971P (trademark) and 2 g of citric acid were added to200 g of erythritol. These were mixed in a mixer for 15 minutes to forma preparation, whereby a suspension capable of being suspended and takenat the time of use is produced. This preparation can be ingested bysuspending a suitable amount (for example, packets corresponding to 10 gor 20 g of erythritol) in water at the time of use.

Example 2 (Granules)

20 g of water was added to 200 g of erythritol and mixed in a mixer. Themixture was mixed in a kneader, then dried at 60° C., then graded by 12mesh and 16 mesh sieves. 2 g of Carbopol 971P (trademark) and 2 g ofmagnesium stearate were added to the granules thus obtained to form agranular preparation. The preparation can be ingested by suspendingpackets containing suitable amounts in water at the time of use.

Example 3 (High Density Granules)

A high density granular preparation was prepared without using water byextruding (1 mm diameter) 200 g of erythritol, 2 g of xanthane gum, and2 g of calcium stearate using an extruder (Kurimoto Tekko). Thepreparation can be ingested by suspending packets containing suitableamounts in water at the time of use.

Example 4 (Preparation of Spherical Granules)

75 g of ethanol was added to 285 g of erythritol (100 mesh sievedproduct) and 15 g of anhydrous citric acid (100 mesh sieved product) andthe mixture kneaded using a Shinagawa type universal mixer to prepare apaste. Next, this paste was extruded and granulated in a basket typegranulator equipped with a 0.6 mm screen (die) to prepare crudegranules. The crude granules thus obtained were transferred to a highspeed mixing, agitating, and granulating device (high speed mixerFS-GS-10J, Fukae Kogyo K. K.) having a spherical granulating diskattached to the agitator and a granulating blade attached to a chopper.The device was operated for 30 seconds at a speed of 200 rpm of theagitator and 2000 rpm of the chopper to make the granules spherical.These were dried at 60° C. for 2 hours, then passed through a 14 mesh(1.18 mm) sieve and graded to a size remaining on a 42 mesh (0.35 mm)sieve to prepare a granular preparation (spherical granules).

INDUSTRIAL APPLICABILITY

The medicine for the treatment of Meniere's disease according to thepresent invention has the advantage of a much easier administrationcompared with isosorbide in terms of taste. Further, erythritol isnoncarious and has zero calories, and therefore, there is the advantagethat there is no concern over cavities or over administration ofcalories. Further, by formulating it as a powder, suspension, orgranules, there is the advantage that less of an amount of the medicineshould be administered compared with Isosorbide and the load on thepatient can be lessened from this viewpoint as well.

What is claimed is:
 1. A method for treating Meniere's diseasecomprising administering a pharmaceutical composition comprising atherapeutically effective amount of erythritol to a patient in needthereof.
 2. The method according to claim 1, wherein the pharmaceuticalcomposition is orally administered.
 3. The method according to claim 1,wherein the erythritol is present in the pharmaceutical composition inan amount ranging from about 90% to about 100% by weight based on thetotal weight of the pharmaceutical composition.
 4. The method accordingto claim 1, wherein the pharmaceutical composition further comprises asuspending agent.
 5. The method according to claim 4, wherein thesuspending agent is present in the pharmaceutical composition in anamount ranging from about 0.1% to about 10% by weight, based on thetotal weight of the pharmaceutical composition.
 6. The method accordingto claim 4, wherein the suspending agent is selected from the groupconsisting of polyvinyl pyrrolidone, sodium carboxymethyl cellulose,carboxyvinyl polymer, hydroxylpropyl cellulose, hydroxypropylmetheylcellulose, xanthane gum, gelatin, tragacanth gum, crystalline cellulose,alginate, and agar.